Epilepsy is a common neurological disorder that has a significant impact on the quality of life and imposes a tremendous burden on patients and the healthcare system. Many antiepileptic drugs produce undesirable side effects and a strong need exists for the development of medications that specifically target the molecular defects that lead to seizure generation. Our long-term goal is to facilitate the development of more effective epilepsy treatments through a better understanding of the genetics of epilepsy and the processes that lead to seizure generation. We previously demonstrated that missense mutations in the voltage-gated sodium channel gene, SCN1A, are responsible for Generalized Epilepsy with Febrile Seizures Plus type 2 (GEFSP2). GEFSP2 is an inherited autosomal dominant form of epilepsy that is often characterized by febrile seizures in childhood followed by the development of adult epilepsy. Loss-of-function SCN1A mutations are responsible for Severe Myoclonic Epilepsy of Infancy (SMEI), a debilitating syndrome that includes seizures, ataxia and mental retardation. Affected individuals with the same SCN1A mutation display different types of epilepsy, disease severity and response to medication. We hypothesize that this clinical variability is due to additional genetic factors (modifier genes) that modulate seizure susceptibility. To test this hypothesis and to gain insight into the role of sodium channel dysfunction in epilepsy, we will generate an allelic series of BAC transgenic mice with three different human GEFSP2 mutations. The BAC transgene will also be engineered to enable us to study the biophysical properties of transgene-derived Scn1a channels in neurons without interference from endogenous sodium channels and to restrict the expression of the transgene to discrete brain regions. The mice will be evaluated for spontaneous seizures, seizure susceptibility and altered brain morphology. We will also use the GEFSP2 mice to map genetic modifiers of seizure susceptibility. This study will provide a better understanding of the genetic and molecular factors that underlie seizure generation and aid in the identification of novel targets for therapeutic intervention. The GEFSP2 mice will be a valuable resource and will be made available to the scientific community.